Senescent Cells Make Everything Worse in the Aging Lungs
Here I'll point out a recent open access paper that covers the various ways in which accumulated senescent cells harm the lungs in old age. The count of senescent cells rises with age in all tissues, the consequence of increased cellular damage on the one hand and progressive failure of the immune system to destroy these cells on the other. The presence of these cells is one of the contributing root causes of aging, in fact. They generate a mix of signals known as the senescence-associated secretory phenotype (SASP) that promotes chronic inflammation, destructively remodels the extracellular matrix structures necessary for correct tissue function, and changes the behavior of nearby cells for the worse. When it comes to the lungs, it is already known that senescent cells make people more vulnerable to respiratory infection, and are responsible for loss of elasticity and degraded normal function of structures in the lungs. Further, senescent cells are strongly implicated as a cause of fatal lung diseases such as idiopathic pulmonary fibrosis, due to their harmful effects on tissue structure.
If senescent cells are such a bad deal, why do we have them? The short answer is that evolution tends to produce systems that work well at the outset, during reproductive life span, and then fall over badly later. The antagonistic pleiotropy view of the evolution of aging describes this picture in more detail; in essence there is little evolutionary pressure after the end of reproductive life to select for a biochemistry with improved repair and maintenance. Senescent cells are initially one of the mechanisms that shape a growing embryo, helping to stop growth when growth must end, such as around fingers, or defining the edges of other organs. They also play a short-term role in wound healing. Further, at least initially and in small amounts, cellular senescence can suppress the risk of cancer by halting replication in those cells most at risk of becoming cancerous. Unfortunately, despite the necessary and useful aspects of cellular senescence, the bad behavior of senescent cells in large numbers eventually kills us.
What is to be done about this? The most straightforward approach is to develop targeted cell killing therapies that destroy senescent cells while leaving normal cells alone. Senescent cell clearance has been demonstrated to produce limited rejuvenation in mice, turning back numerous specific aspects of aging and age-related diseases, and a range of approaches to bring this capability to human medicine are currently at various stages of development. Small molecule drugs that trigger apoptosis in senescent cells are the furthest along, and are entering clinical trials this year and next. Beyond that, groups like Oisin Biotechnologies are working on programmable gene therapies and other approaches that should prove more effective than the output of the traditional drug discovery pipeline. This will all cascade into the clinic over the course of the next decade, starting a year or two from now, and given the benefits we should all be putting some funds aside for our own treatment when it becomes available at a reasonable price.
Pneumonia causes significant mortality and morbidity in elderly patients, defined as those aged over 65 years, compared to younger populations. The annual incidence of pneumonia in the elderly populations is 4 times that of younger populations. In addition, the rates of hospitalization for pneumonia increase in elderly patients with each passing year, and with an expected 20% of the world's population reaching elderly status by 2050, the burden of community-acquired pneumonia will be even more significant in the coming years. In the respiratory system, aging might render individuals more susceptible to infection by undergoing various physiological changes, including dilatation of airspaces, increased air trapping, decreased chest wall compliance, reduced respiratory strength, decline in mucociliary clearance, and diminishment of cough reflex. In addition, aging weakens the immune system in conjunction with the presence of comorbid diseases (e.g., diabetes mellitus, chronic heart disease, malignant tumors, and use of immunosuppressive drugs). However, the definitive mechanisms underlying the high morbidity and mortality of pneumonia in elderly populations are not fully understood.
Several lines of evidence indicate that age-associated, nonmicrobial, and chronic low-grade inflammation enhances the susceptibility of pneumonia in the elderly populations. A previous study reported that elevated tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels positively correlated with the incidence of pneumonia in healthy elderly individuals. Other studies demonstrated that aged mice had increased lung inflammation and were found to be highly susceptible to pneumococcal pneumonia.
Cellular senescence, one of the hallmarks of aging, carries out its primary duty as a trigger of tissue repair, regeneration, and remodeling during normal embryonic development and upon tissue damage. To eliminate damaged cells, senescent cells arrest their own proliferation, create an inflammatory microenvironment, recruit phagocytic immune cells for elimination of senescent cells through senescence-associated secretory phenotype (SASP), and promote tissue renewal. These processes are beneficial for organisms in young tissue where the sequence of senescence-clearance-regeneration is transient in manner. However, this beneficial processes can be corrupted in a pathological context and aged tissues, where senescent cells persistently accumulate. The combination of senescent cell accumulation and excessive SASP results in persistent low-grade inflammation in aging tissue, which elevates the susceptibility to pathogen threats. Furthermore, accumulation of senescent cells causes disruption of normal tissue microenvironments and aberrant tissue remodeling through extracellular matrix (ECM) degeneration and tissue fibrosis.
In the respiratory system, emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related diseases and increase the vulnerability to pneumonia. Both of the diseases bear the feature of chronic low-grade inflammation with upregulations of various growth factors and chemokines. Thus, it is speculated that COPD and IPF might enhance the vulnerability to pathogens not only by their structural collapse of lung parenchyma, which makes it easier for pathogens to invade, but also by inducing chronic low-grade inflammation due to SASP. Since both of the lung disorders predominantly affect the elderly and have a lot of involvement in the susceptibility to the pathogens, we contemplate that it is also important to focus on the involvement of cellular senescence in the pathogenesis COPD and IPF for getting to the core of elderly pneumonia.